The ubiquitin proteasome system (UPS) is one of the key protein degradation pathway involved in the control of protein homeostasis and turnover that mediates the regulation of several cellular processes. The UPS consists of two separate consecutive steps, ubiquitination and proteasomal degradation. Due to its involvement in multiple metabolic and regulatory functions, the UPS is considered as a vital part of the cellular machinery controlling protein homeostasis. Targeting specific components of the UPS in order to regulate cellular growth and metabolism in diseases is not a novel concept; however, advances in molecular signalling have revealed a number of potential enzyme targets within the UPS that, if successfully modulated, can lead to the development of highly specific drugs against a number of pathological and degenerative disease indications.
Many scientists and research groups are trying to unravel the hidden potential of this highly complex regulatory system in order to develop viable drug candidates. According to PubMed, there are close to 1500 publications related to ubiquitin enzymes from 2015 till date. A number of technical advances in this domain have led to the development of multiple technology platforms, research based assays, toolkits, probes, reagents and precursor compounds to support the different drug discovery programs of various academic and industry researchers. In fact, the current market landscape features contributions of not only big pharma companies but also small to mid-sized players and academic institutions.
A number of strategic partnerships have also been inked between various stakeholders to advance R&D activities in this domain. Results of preclinical and clinical studies have demonstrated the potential benefits of this class of therapies; the major highlight being their attractive safety profile. The burgeoning field of research has captured the interest of several venture capital firms and strategic investors. The upcoming market, primarily focused on oncological indications, is expected to prosper in the long term and witness the emergence of several successful drugs.
SCOPE OF THE REPORT
The "Ubiquitin Enzymes: Key Targets and Future Market Potential, 2016-2030" report provides an extensive study on the current landscape of the evolving pipeline of ubiquitin enzyme inhibitors and offers a comprehensive discussion on the future potential of this market. Ubiquitin enzymes have been implicated in various cellular processes, such as protein homeostasis, apoptosis, autophagy, DNA damage repair, cell cycle control and senescence. Due to their involvement in multiple metabolic and regulatory functions, any deviations in the normal functioning of the UPS has been shown to lead to the development of diverse types of diseases.
Initial research on the UPS led to the development of several proteasome inhibitors, such as Velcade®, Kyprolis® and Ninlaro®, which are already available in different regions across the globe. However, since these drugs target the entire protein degradation pathway, lack of target specificity renders them potentially harmful and their use has been shown to pose side effects in patients. Consequently, the focus is gradually shifting from proteasome inhibitors to targeting specific components of the UPS, primarily on ubiquitination enzymes. This is a relatively new segment of the overall market. With no marketed products, the UPS associated enzyme inhibitors / modulators market is still in its infancy. The report primarily focuses on four classes of enzymes that have been shown to possess therapeutic relevance; these include E1 activating enzymes, E2 conjugating enzymes, E3 ligases and deubiquitinases (DUBs).
Currently, the ubiquitin pathway based inhibitors pipeline comprises of over 45 molecules that are under development for the treatment of a variety of indications. In addition, there are several companies that are engaged in the development of screening and validation assays for lead selection, research tools and competent technologies in this field. This unexploited and promising market has its hopes pinned on multiple start-ups, which have received significant financial support from several strategic investors and venture capital firms over the last few years. Among other elements, the report provides the following information:
- The current state of the market with respect to the key players, phase of development of pipeline products (both clinical and preclinical / discovery), target enzyme classes and the key disease indications.
- Comprehensive profiles highlighting clinical trial details, key preclinical / clinical findings and future market opportunity for the clinical stage (phase I/II, phase II and phase III) ubiquitin enzyme inhibitors.
- Various investments and grants received by companies focused in this area in order to accelerate and support their R&D activities.
- Partnerships that have taken place in the recent past covering product development / commercialization agreements, research collaborations, clinical trial collaborations, license agreements, acquisitions and other such deals between stakeholders in the industry.
One of the key objectives of this report was to understand the current activity and the future potential of the market. The study provides a detailed market forecast and opportunity analysis for the period between 2016 and 2030. The research, analysis and insights presented in this report include a detailed description of ubiquitin enzyme inhibitors along with drug classes closely associated with them. To add robustness to our model, we have provided three scenarios for our market forecast, namely the conservative, base and optimistic scenarios, to account for future uncertainties. The opinions and insights presented in this study were influenced by several discussions conducted with experts in this domain. All actual figures have been sourced and analyzed from publicly available information forums and from primary research. All financial figures mentioned in this report are in USD, unless otherwise specified.
Most of the data presented in this report has been gathered via secondary and primary research. For all our projects, we conduct interviews with experts in the area (academia, industry, medical practice and other associations) to solicit their opinions on emerging trends in the market. This is primarily useful for us to draw out our own opinion on how the market will evolve across different regions and technology segments. Where possible, the available data has been checked for accuracy from multiple sources of information.
The secondary sources of information include
- Annual reports
- Investor presentations
- SEC filings- Industry databases
- News releases from company websites
- Government policy documents
- Industry analysts' views
While the focus has been on forecasting the market over the coming ten years, the report also provides our independent view on various non-commercial trends emerging in the industry. This opinion is solely based on our knowledge, research and understanding of the relevant market gathered from various secondary and primary sources of information.
Chapter 2 presents an executive summary of the report. It offers a high level view on where the ubiquitin enzyme inhibitors market is headed in the mid-long term.
Chapter 3 provides a general introduction to the underlying concepts of protein homeostasis, emphasizing on the importance of post translational modifications in cellular processes. The chapter covers details on the discovery of the UPS, the structure and function of ubiquitin, brief discussions on the various components of the UPS, fundamentals of the UPS machinery and a schematic representation of the ubiquitination process. In addition, we have discussed the therapeutic applications of the UPS, providing the necessary arguments and evidence supporting the gradual replacement of the currently available proteasome inhibitor based therapies with the emerging class of ubiquitin enzyme inhibitors.
Chapter 4 provides a comprehensive overview of the current landscape of the ubiquitin enzyme inhibitors market. It includes information on the potential drug candidates that are currently in different stages of development (both clinical and preclinical / discovery). It presents a detailed analysis of the pipeline of products in this domain, including information on the most commonly targeted indications, current phases of development, target enzyme classes and key players involved in this space. Additionally, we have provided details of several research platforms, precursor compounds and research tools developed / being developed by various companies in order to support R&D initiatives in this space.
Chapter 5 presents important insights extracted from the current pipeline. The chapter provides a grid analysis of the candidate drugs in the market based on their distribution by target enzyme class, therapeutic area and highest phase of development. It also highlights the most popular targets within the UPS pathway from among the four ubiquitin enzyme classes mentioned earlier. In addition, we have also included an overview of the developer landscape based on the size and the activity of the industrial / non-industrial players engaged in this market. Along with that, we have mapped the geographical presence of various companies involved in the clinical development of product candidates in this field.
Chapter 6 focuses on E1 activating enzyme and E2 conjugating enzyme based inhibitors. The chapter includes a brief discussion on the role of these enzymes in the UPS pathway, including their mechanisms of action, important enzyme families, targets under investigation, current challenges and opportunities, and other relevant parameters. The chapter also includes detailed profiles of advanced stage product candidates. Each profile covers information such as drug specifications, its mechanism of action, current status of development, ongoing / completed clinical studies, key preclinical / clinical findings and other associated details.
Chapter 7 provides in-depth information on E3 ligases. The chapter includes a brief discussion on the role of E3 ligases in the UPS pathway, including its mechanism of action, important enzyme families, targets under investigation, current challenges and opportunities, details of screening assays and other relevant parameters. The chapter also includes detailed profiles of advanced stage product candidates. Each profile covers information such as drug specifications, its mechanism of action, current status of development, ongoing / completed clinical studies, key preclinical / clinical findings and other associated details.
Chapter 8 elaborates on DUB enzyme inhibitors. As in earlier two chapters, it discusses the role of DUBs in the UPS pathway, including its mechanism of action, important enzyme families, targets under investigation, current challenges and opportunities, details of screening assays and other relevant parameters. The chapter also includes detailed profiles of the drugs under advanced stages of development.
Chapter 9 provides details on the various drug classes that are closely related to the UPS; these include proteasome inhibitors, immunomodulatory drugs (IMiDs) and inhibitors of apoptosis proteins (IAP inhibitors). In this section, we have provided a brief introduction to the aforementioned competing drug classes, providing insights into their respective mechanisms of action and an overview of the molecules developed / being developed under each class of drugs.
Chapter 10 presents details on the investments and grants received by companies working in the field of ubiquitin enzymes and other closely associated product candidates. The analysis highlights the growing interest of the venture capital community and other strategic investors in this market.
Chapter 11 features an elaborate discussion on the collaborations and partnerships that have been inked amongst players in this market. We have also discussed the various partnership models that have been implemented, highlighting the most common forms of deals / agreements prevalent in this segment of the overall market.
Chapter 12 provides a comprehensive market forecast analysis, highlighting the future potential of the market till the year 2030. The analysis takes into consideration the molecules that are in relatively more advanced stages of development (phase I/II, phase II and phase III). The future sales potential and growth opportunity is based on the target patient populations, existing / future competition, likely adoption rates and price points.
Chapter 13 summarizes the overall report. In this chapter, we have provided a recap of the key takeaways from the study and our independent opinion based on the research and analysis described in previous chapters.
Chapter 14 is a collection of interview transcripts of the discussions that were held with key stakeholders in this market. We have presented the details provided to us by Martin Wiles (Vice President, Almac Discovery) and Gerald Gavory (Director of Biology, Almac Discovery), Zhihao Zhuang (Associate Professor, Department of Chemistry and Biochemistry, University of Delaware) and Katrin Rittinger (Research Group Leader, Francis Crick Institute).
Chapter 15 is an appendix, which provides tabulated data and numbers for all the figures provided in the report.
Chapter 16 is an appendix, which provides the list of companies and organizations mentioned in the report.
1. Over 45 molecules targeting ubiquitin enzymes are currently in clinical / preclinical stages of development. 71% of the pipeline molecules are targeting oncological indications. Within oncology, hematological malignancies, such as acute myeloid leukemia (AML) and relapsed / refractory multiple myeloma (MM), are the primary focus areas. In fact, the two late stage molecules, idasanutlin and pevonedistat, are being developed for hematological cancers. Other indications such as Alzheimer's disease, Parkinson's disease, Friedreich's ataxia and Angelman syndrome are also gradually gaining interest of developers.
2. The innovation in this emerging field is primarily being led by start-ups / small companies. Notable examples include (in alphabetical order) Agilis Biotherapeutics, Aileron Therapeutics, Almac Discovery, Aperion Biologics, Ascenta Therapeutics, Carmot Therapeutics, CellCentric, Cleave Biosciences, Ensemble Therapeutics, Mission Therapeutics, Progenra, Proteostasis Therapeutics, UbiQ Therapeutics, and Vivolux. In addition, a number of large companies are also developing assets in this field. Prominent players under this category include (in alphabetical order) Amgen, Biogen, Daiichi Sankyo, Merck, Novartis Pharmaceuticals, Priaxon, Roche / Genentech, Sanofi and Servier.
3. Prominent academic players, including (in alphabetical order) the Dana-Farber Cancer Institute, Karolinska Institute, Mayo Clinic, Memorial Sloan Kettering Cancer Center, University of Oxford and University of Michigan, have entered into research collaborations with industry players to conduct further research for the development of various inhibitors.
4. Several strategic investors and venture capitalists have strongly backed the potential offered by this domain. We identified over 70 funding instances over the past few years. The total amount invested has been close to USD 1.2 billion; of this, 70% has been invested during the last five years alone.
5. Stakeholders have actively collaborated to advance R&D initiatives. We came across 72 collaborations categorized as product development / commercialization agreements, product licensing agreements, technology licensing, acquisitions, clinical trial agreements and research collaborations. Among these, development / commercialization agreements and research collaborations, with over 60% share, have been the most popular.
6. In addition, we came across around 20 technology / research platforms that are currently available to advance the development of ubiquitin enzyme inhibitors. It is worth mentioning that these platforms are a direct consequence of the intense research activity in this field. Examples include (in alphabetical order) DUBprofiler™, DUBprofiler™, PROTAC Technology Platform, Ubi-Plex™ and UbiPro™.
7. Overall, we expect the field to witness considerable success in the long term. Post the launch of the first wave of products, we predict the market to grow at an annualized rate of 71% till 2030.
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